Solubilization of poorly water soluble drugs is essential for the delivery of the drugs by oral or parenteral administration. There are several conventional methods for solubilization of poorly water soluble drugs. For example, a poorly water soluble drug may be dissolved in a mixture of a water-miscible organic solvent and water. Alternatively, structural modification of a poorly water soluble drug from its acid or base to its salt form may increase the water solubility of the drug. Other methods include complexation of a poorly water soluble drug with a third substance or entrapment of a poorly water soluble drug into micelles formed by a surfactant. See Leon Lachman, “The theory and practice of industrial pharmacy”, Lea & Febiger, Philadelphia, 1986.
Among the above methods, the micelles formed by use of a surfactant may be manufactured to have a size of several nm to several μm, and may be finely dispersed in an aqueous solution. Therefore, use of micelles has been preferred for the solubilization of poorly water soluble drugs.
Surfactants have a chemical structure comprising a hydrophilic block and a hydrophobic block, wherein the hydrophilic block has high affinity for water on one side and the hydrophobic block, has a high affinity for oil on the other side. If the hydrophilic block is dominant, the surfactants dissolve better in water, and conversely, if the hydrophobic block is dominant, the surfactants dissolve better in an organic solvent. Surfactants are classified into ionic and non-ionic. In the method of solubilization for a poorly water soluble drug, the non-ionic surfactant does not affect the poorly water soluble drug through ionic interactions due to its electronic neutrality. Such surfactants include anion salts of fatty acid derivatives, sorbitan derivatives such as Tween or Span, polyoxyethylene monoalkylether derivatives (BRIJ and MYRJ series) and polyethylene glycol ester derivatives of fatty acids, polyoxyethylated caster oil derivatives such as Cremophor, etc., and the like.
EP 0,645,145 discloses a method in which paclitaxel, a poorly water soluble drug, is solubilized using Cremophor EL which is a non-ionic surfactant. However, the drug solubilized by the surfactant has limited use due to adverse side effects, such as hypersensitive reactions, when it is administered orally or parentally. It also has the drawback in that the drug is separated from the micelles when stored for a long time since the stability of the micelles in an aqueous solution is very low.
Use of a polymeric micelle made of a di- or tri-block copolymer comprising a hydrophilic polymer of polyalkylene glycol derivatives and a hydrophobic biodegradable polymer such as fatty acid polyesters or polyamino acids for solubilization of a hydrophobic drug has been reported. For example, U.S. Pat. No. 5,449,513 discloses a diblock copolymer comprising a polyethylene glycol as the hydrophilic polymer, and a polyamino acid derivative, e.g. polybenzyl aspartic acid, etc., as the hydrophobic polymer. The diblock copolymer can solubilize hydrophobic anticancer agents, e.g. doxorubicin, or anti-inflammatory agents, e.g. indomethacin. However, the drawback is that the polyamino acid derivative is not hydrolyzed in vivo and causes undesired side effects.
Furthermore, U.S. Pat. No. 5,429,826 discloses a di- or multi-block copolymer comprising a hydrophilic polyalkylene glycol and a hydrophobic polylactic acid. Specifically, the above patent describes a method for stabilization of a polymeric micelle by micellizing a di- or multi-block copolymer having an acrylic acid terminal group in an aqueous solution, and then, crosslinking the micelle. Although this method may improve the stability of the polymeric micelles, the drawback is that the crosslinked polymer is not degraded, and thus, cannot be applied for in vivo use.
Polylactic acid has been applied for drug delivery systems in various forms because it has an excellent biocompatibility and biodegradability. Polylactic acids have various properties depending on their molecular weight, and have been developed in various formulations such as microspheres, nanoparticles, polymeric gels, implant agents, and the like. However, polylactic acids having a molecular weight of more than 2,000 Daltons are not dissolvable in aqueous solutions. There has been no reported success in developing polylactic acids having molecular weights of less than 2,000 Daltons as drug delivery systems since they are not dissolvable in an aqueous solution of a pH of 4 or more.
In view of the foregoing, development of an improved polymeric micelle composition for hydrophobic drug delivery, that is biocompatible and biodegradable, will be appreciated and desired. The present invention provides for such an improved polymeric micelle composition, which is biocompatible and biodegradable, and which can effectively deliver a hydrophobic drug without a decrease in its stability.